TOX-induced lnc-SUMF2-8 compromises antitumor function and anti-PD-1 response of CD8+ T cells via lysosome-dependent degradation of TCF-1

Abstract

The reduction of TCF-1 during CD8⁺ T cell exhaustion leads to attenuated antitumor activity and diminished responsiveness to immune checkpoint inhibitors. However, how TCF-1 is downregulated remains unclear. Here, we showed that during CD8⁺ T cell exhaustion, lnc-SUMF2-8, induced by transcription factor TOX, can bind to cytosolic TCF-1 and direct it to the lysosome for degradation. The reduction of TCF-1 promotes Tex^prog differentiation into Tex^int/eff and further drives functional Tex cells into a fully dysfunctional Tex^term state. We demonstrated that TCF-1 reduction during T cell exhaustion is initiated by lnc-SUMF2-8-dependent lysosomal degradation of TCF-1 protein, followed by transcriptional suppression of TCF7 mRNA. Deletion of lnc-SUMF2-8 blocks lysosomal TCF-1 degradation, which maintains stable TCF-1 levels in Tex cells, thereby expanding the anti-PD-1-responsive Tex^prog cells and enhances the persistence of functional CD8⁺ T cells. Our findings suggest that targeting lnc-SUMF2-8 could enhance the function of the antitumor CD8⁺ T cells and synergistically improve the efficacy of anti-PD-1 treatment and CAR-T cell therapies.

Keywords: T cell exhaustion; TCF-1; anti-PD-1 response; hepatocellular carcinoma; lnc-SUMF2-8.